Research Progress and Adhesion Mechanisms of Medical Tissue Adhesives

Currently, surgical sutures/staples are primarily employed in clinical settings to close wounds and surgical incisions, aiming to achieve hemostasis, wound sealing, provide an antibacterial barrier, and facilitate tissue healing. However, suturing may damage fragile tissues, increase the risk of bacterial infection, be time-consuming, and require a high level of technical proficiency. Medical tissue adhesives have garnered significant attention in the medical field due to their remarkable advantages, including ease of operation, non-invasive adhesion, immediate sealing and hemostasis, and effective reduction of surgical time. They are gradually becoming effective adjuncts or alternatives to traditional surgical sutures. Ideal raw materials for medical tissue adhesives typically possess excellent biocompatibility, biodegradability, good mechanical strength, and adhesive force, and meet the following requirements: (1) They must be safe and non-toxic, with good biocompatibility, causing no allergic or toxic reactions; (2) They should possess good adhesion properties, enabling rapid adhesion of tissues under physiological conditions to achieve timely wound closure and hemostasis; (3) They must exhibit good biodegradability with an appropriate degradation rate, and their degradation products should be non-toxic and side-effect-free; (4) They should maintain good mechanical properties under physiological conditions; (5) They should be easy to handle and convenient to store; (6) They should be cost-effective and straightforward to produce.

Based on the primary sources of their constituent materials, medical tissue adhesives can be categorized into two broad groups: natural materials and synthetic materials. Natural material-based medical tissue adhesives generally exhibit excellent biocompatibility and biodegradability. However, their raw materials tend to be costly, difficult to store, and may have limited mechanical strength and adhesive strength. Additionally, they possess potential pro-inflammatory and immunogenic properties, which to some extent restrict their widespread use. Fibrin-based tissue adhesives are currently the most widely used natural material tissue adhesives in clinical practice. They achieve hemostasis through the conversion of fibrinogen into fibrin clots while simultaneously crosslinking with tissues to achieve adhesion. Fibrin-based adhesives possess strong biodegradability and biocompatibility, typically not triggering inflammatory responses. However, their relatively poor mechanical strength and low adhesive force can limit their practical clinical applications. Furthermore, due to their specific origin, fibrin-based adhesives carry a potential risk of disease transmission. Currently, fibrin-based adhesives are mostly used in surgeries such as plastic surgery, skin transplantation, otolaryngology, head and neck surgeries, and pulmonary air leaks.

Medical tissue adhesives prepared from synthetic materials generally offer high controllability, enabling precise adjustment of their mechanical strength, adhesive strength, and degradation rate according to the specific application to achieve optimal adhesion effects. Synthetic material adhesives exhibit stronger mechanical properties compared to natural material adhesives. However, they typically have poorer biocompatibility due to a lack of cellular recognition and binding sites. Furthermore, they may also present issues such as cytotoxicity, chronic inflammation, and difficulty in degradation within the body. Cyanoacrylate-based tissue adhesives are currently the most widely used synthetic material tissue adhesives in clinical practice. Their rapid polymerization speed and strong adhesive force, combined with the polar groups -CN and -COO^- in their chemical structure, serve as the primary sources of reactivity, enabling them to form covalent bonds with amino groups in tissues, thereby achieving tissue adhesion. Currently, cyanoacrylate-based tissue adhesives are primarily used in surgeries such as thoracic, gastrointestinal, neurosurgical, cardiovascular, and ophthalmic procedures. However, cyanoacrylate-based adhesives also have limitations. Firstly, the presence of water molecules can cause the adhesive material to cure, leading to a near-complete loss of adhesive strength in conditions with significant amounts of bodily fluids. Secondly, the exothermic polymerization reaction of cyanoacrylates can cause thermal damage to tissues and may even leave scars. Thirdly, the production of byproducts such as formaldehyde during the use of cyanoacrylate-based adhesives raises concerns about their cytotoxicity and potential toxicity.

Currently, scholars have developed numerous tissue adhesive technologies and prepared related tissue adhesive products. Since the 1970s, the US FDA and European CE have approved the clinical use of tissue adhesives. The approved tissue adhesives include biological tissue adhesives such as gelatin-based, fibrin-based, and albumin-based, as well as chemically synthesized tissue adhesives such as polyethylene glycol-based and cyanoacrylate-based. The details are shown in the following table (source: literature [1]).

Adhesive Mechanism of Tissue Adhesives

The adhesion of tissue adhesives on tissues is achieved through both physical and chemical interactions. Physical interactions encompass mechanical interlocking, ionic interactions, hydrogen bonding, electrostatic interactions, hydrophobic effects, and diffusion. In contrast, chemical interactions occur through chemical reactions with functional groups on the tissue surface, such as amino, thiol, and carboxyl groups. During the actual adhesion process, most medical tissue adhesives primarily rely on chemical crosslinking, combined with other types of adhesion mechanisms, to achieve wound closure and hemostasis.

1. Chemical Interactions

Chemical bonding is the primary mechanism responsible for the adhesion between medical tissue adhesives and tissues. Once the adhesive comes into contact with the surface of the substrate tissue, various types of chemical bonds (such as covalent bonds, ionic bonds, and metallic bonds) can form between the molecules at the interface, providing strong adhesion. Common interfacial chemical bonding includes crosslinking reactions between adhesive modified with functional groups like active esters (e.g., N-hydroxysuccinimide, NHS), isocyanates, and aldehydes, and primary amine groups on the surface of biological tissues. For instance, the aldehyde group in oxidized chondroitin sulfate can react with amino groups on tissues to form Schiff bases, and this reaction principle can be utilized to introduce chondroitin sulfate into gelatin to prepare injectable gelatin-based hydrogel adhesives. Catechol groups, by mimicking the structure of the adhesive amino acid 3,4-dihydroxyphenylalanine (DOPA) found in mussel adhesive proteins, also exhibit high reactivity. A significant number of catechol-modified medical tissue adhesives can firmly adhere to various polymer materials, metal materials, and biological tissue surfaces.

2. Mechanical Interlocking

Mechanical interlocking refers to the adhesion formed when the adhesive material penetrates the surface and mechanically interlocks with the micro-pores or irregularities on the surface of the substrate material. For example, in traditional dental cavity filling procedures, amalgam alloys firmly adhere to the pretreated rough tooth surface through mechanical interlocking. In nature, an endoparasitic worm known as the spiny-headed worm uses its long proboscis to penetrate tissue and firmly attach to the intestinal wall of its host. By mimicking the adaptive morphology of the worm's proboscis, researchers have developed a structured biphasic microneedle (MN) that achieves robust adhesion through mechanical interlocking between the expandable microneedle tips and tissue. In skin graft fixation experiments, these smooth conical needles can be inserted into tissue in a dry state, minimizing the force required for tissue penetration. Upon contact with water, the needle tips swell, rapidly increasing their cross-sectional area, leading to local tissue deformation and subsequent mechanical interlocking. This bioinspired MN medical tissue adhesive is capable of robust adhesion to various wet tissues, such as skin and intestinal tissue, in dynamic environments.

3. Diffusion

When the adhesive and substrate surface are mutually soluble, and their polymer chains possess sufficient mobility, the polymer network can penetrate, diffuse, and entangle at the adhesion interface. As highly hydrated conditions favor polymer diffusion, this mechanism may be limited to bioadhesives designed for use in environments with high moisture content, such as blood vessels or the digestive tract. For instance, researchers have developed diffusive medical tissue adhesives (DAs) composed of a hydrogel matrix, preloaded water-soluble monomers, and crosslinkers. Upon contact with the substrate surface, the polymers can extensively diffuse into the water-rich substrate interior, subsequently initiating monomer polymerization and crosslinking to form a bridging network that interpenetrates and binds the adhesive and substrate skeletons together, maximizing the contact area between the adhesive and substrate. This adhesive exhibits high strength and toughness even without the formation of covalent bonds, and its adhesion strength can be precisely adjusted by controlling the diffusion profile.

4. Hydrogen Bonding

Hydrogen bonding occurs when a hydrogen atom is bound to two electronegative atoms, which in biological systems are typically oxygen or nitrogen. The strength of hydrogen bonds varies depending on the environment, but it is still lower than that of chemical bonds. However, when a large number of hydrogen bonding sites exist between the adhesive and tissue, hydrogen bonding becomes a significant contributor to adhesion strength. For example, tannic acid, a polyphenolic substance, can be crosslinked with gelatin methacrylate hydrogels to enhance the adhesion performance of the resulting tissue adhesive by strengthening hydrogen bonding interactions.

5. Electrostatic Interactions

Ionic adhesives carrying positive or negative charges can bind to substrate surfaces with opposite charges through electrostatic interactions. The molecular composition of biological tissue surfaces is inherently complex, encompassing both positively and negatively charged, polar, and nonpolar groups. Researchers have developed a polyzwitterionic hydrogel adhesive that can bind to positively or negatively charged polyelectrolyte hydrogel substrate surfaces via electrostatic interactions. Since biological tissues are primarily composed of polyelectrolytes (such as polysaccharides on cell surfaces) and polyzwitterions (like proteins), this polyzwitterionic hydrogel adhesive can also form numerous electrostatic binding sites with various tissue surfaces, exhibiting exceptional biological adhesion properties.

References

[1] Zhang Weijie, Zhang Bing, Wang Yihu, et al. Research Progress of Medical Tissue Adhesives [J]. Gelatin Science and Technology, 2021(004): 041.

[2] Zhu Haofang, Mao Hongli, Gu Zhongwei. Research Progress of Medical Tissue Adhesives [J]. Materials China, 2020, 39(Z1): 535-550+557-558.  

About the Author

Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.